Download Parkinsonian Treatments and L-Dopa vs. D

Parkinsonian Treatments and L-Dopa vs. D-Dopa
Dopamine, a chemical molecule which derives its name from an amine group
attached to a dihydroxyphenylalanine (dopa-amine), is a neurotransmitter produced in
the substantia nigra and the ventral tegmental area of the brain.
Figure 1: Dopamine
The main role of dopamine is in reward- driven learning. Every time the brain
experiences a reward, the dopamine levels in the brain elevate (Yavich, 2007). This also comes in to play
with addiction. Many addictive drugs, act directly on the dopamine system—thus, when a person “gets
high”, they feel rewarded for their actions, and therefore, continue to take the drug.
Dopamine is the key neurotransmitter affected in Parkinson’s disease—a degenerative disorder
that causes tremor and motor impairment. This degeneration is caused by the loss of dopaminesecreting neurons in the substantia nigra.
Common treatments of Parkinson’s have been the use of the levodextrorotary
form of dopamine, otherwise known as L-Dopa (L-3,4-dihydroxyphenylalanine). This is
the precursor to dopamine. It is given to Parkinsonian suffers in order to increase
Figure 2: L-Dopa
dopamine concentrations in the brain; however, initially it was believed to be a biologically inactive
molecule.
A study done by O. Hornykiewicz from the University of Vienna declared this to be false. Interest
was sparked in the L-dopa molecule after a discovery in 1938 that L-dopa was enzymatically converted
to dopamine in the animal and human body (Hornykiewicz, 2002). By the 1960s, it was determined that
L-dopa was a successful treatment for those suffering with Parkinson’s Disease.
Dextrodopa (D-3,4-dihydroxyphenylalanine), or D-Dopa, has the opposite
chirality of L-Dopa, and it too was initially believed to be biologically inactive. However,
it was found in 1988 in a study conducted by Karoum, Freed, Chuang, Cannon-Spoor,
Figure 3: D-Dopa
Wyatt, and Costa that rats with lesioned in their substantia nigra were injected with Ddopa in combination with carbidopa, increased dopamine concentration in the striatum to the same
concentration as a similar treatment as L- Dopa plus carbidopa. It was found that although dopamine
concentrations in the lesioned striata area, there was a significant increase in dopamine metabolites,
which concludes that some form of extraneuronal form of dopamine was present. This suggest that DDopa can be converted to dopamine in a striatum that is devoid of dopamine nerve terminals, and that
D- and L-Dopa produced a change in dopamine levels with similar efficacy. This turning behavior was
attributed to the stimulation of sensitive dopamine receptors in the lesioned striata by the
extraneuronally formed dopamine. D-Dopa was converted to dopamine via transamination and/or Damino acid oxidation to the 3,4-dihydroxyphenylalanine form.
It was noted in the study that D-Dopa onset of turning was delayed as compared with L-Dopa.
This slow onset result suggests that the use of racemic mixture of DOPA combined with a peripheral
dopadecarboxylase inhibitor may be more effective in the treatmen of Parkinson’s Disease as opposed
to L- or D-dopa alone.
Resources:
Hornykiewicz, O. 2002. “L-DOPA: from a biologically inactive amino acid to a successful therapeutic
agent” Amino Acids. 23 (1-3): 65-70.
Karoum F., Freed WJ., Chuang LW., Cannon-Spoor E., Wyatt RJ., Costa E. 1988. “D-Dopa and L-Dopa
Similarly Elevate Brain Dopamine and Produce Turning Behavior in Rats.” Brain Res. 440(1):190
Yavich, L., Forsberg, M. M., Karayiorgou, M., Gogos J.A., Mannisto, P. T. Sept. 2007. “Site-Specific Role
of Catechol-O-Methyltransferase in Dopamine Overflow within Prefrontal Cortex and Dorsa
l Striatum”. The Journal of Neuroscience. 27(38): 10196 - 10209